The level of resistance to infection in inbred mice with the murine malaria species Plasmodium chabaudi AS is genetically determined. Resistant C57BL/6, which are able to eliminate the parasite by 4 weeks, develop marked splenomegaly and survive the infection. Susceptible A/J mice, which succumb to infection (mean survival time = 10 days), develop only minimal splenomegaly. In order to determine if gross differences in the organization, number, and type of spleen cells are related to the outcome of infection with P. chabaudi AS, the development of splenomegaly was examined by enzyme and immunohistochemical methods during the first week after infection. Cryostat sections of spleens removed from normal animals of both strains and at 4 and 7 days after intraperitoneal infection with 10(6) parasitized erythrocytes were stained for enzyme (acid phosphatase and nonspecific esterase) and immunohistochemistry with conventional monoclonal antibodies against T cells, B cells, and macrophages as well as with novel rat anti-mouse monoclonal antibodies which define discrete subpopulations of macrophages in the mouse spleen. The livers of normal and infected animals of each strain were also examined. The results of this study demonstrate (1) differences between normal, uninfected B6 and A/J mice in the organization and number of one subpopulation of macrophages in the spleen, the marginal metallophilic macrophages, and (2) marked histological changes in the spleen and liver during the course of infection in both resistant C57BL/6 and susceptible A/J mice. These changes include depletion of cells from the marginal zone of the spleen which, in the case of the marginal metallophilic macrophages, appears to be more severe in susceptible A/J mice.